Daily Endocrinology Research Analysis
Three impactful endocrinology papers stand out today: a randomized crossover trial shows empagliflozin reduces urinary stone-forming supersaturation in nondiabetic adults; a Nature Metabolism study identifies a feeding-induced myokine (feimin) that regulates glucose via MERTK; and a nationwide Danish cohort links prenatal systemic glucocorticoid exposure to elevated risks of neurodevelopmental and mood/anxiety disorders in offspring.
Summary
Three impactful endocrinology papers stand out today: a randomized crossover trial shows empagliflozin reduces urinary stone-forming supersaturation in nondiabetic adults; a Nature Metabolism study identifies a feeding-induced myokine (feimin) that regulates glucose via MERTK; and a nationwide Danish cohort links prenatal systemic glucocorticoid exposure to elevated risks of neurodevelopmental and mood/anxiety disorders in offspring.
Research Themes
- SGLT2 inhibitor repurposing beyond diabetes
- Myokine signaling and glucose homeostasis
- Prenatal glucocorticoid exposure and neurodevelopmental risk
Selected Articles
1. A feeding-induced myokine modulates glucose homeostasis.
This study identifies feimin, a feeding-induced myokine, as a regulator of glucose homeostasis. Feimin binds MERTK to activate AKT, increasing glucose uptake and suppressing hepatic glucose production; co-administration with insulin synergistically improves glycaemia in mice. A human MERTK variant (R466K) reduces feimin binding and associates with higher postprandial glucose and insulin.
Impact: It reveals a previously unknown myokine–receptor axis (feimin–MERTK) with direct translational hooks via human genetics and pharmacological synergy with insulin.
Clinical Implications: While preclinical, feimin–MERTK could become a therapeutic target or biomarker to augment postprandial glucose control. The MERTK R466K variant may stratify individuals with impaired feimin signaling.
Key Findings
- Identification of feimin, a feeding-induced myokine secreted by skeletal muscle.
- Feimin binds MERTK and activates AKT to enhance glucose uptake and suppress glucose production.
- Feimin plus insulin synergistically improves glycaemia in mice.
- Human MERTK R466K variant reduces feimin binding and associates with elevated postprandial glucose and insulin.
Methodological Strengths
- Multimodal evidence across in vivo mouse models, cellular assays, and human genetic association.
- Mechanistic pathway delineation (MERTK–AKT) with functional readouts.
Limitations
- Preclinical study; efficacy and safety in humans are untested.
- Breadth of metabolic effects and tissue specificity beyond skeletal muscle require clarification.
Future Directions: Validate feimin–MERTK signaling in humans (pharmacokinetics, target engagement) and assess therapeutic modulation in metabolic disease models and early-phase clinical trials.
Maintaining blood glucose homeostasis during fasting and feeding is crucial for the prevention of dysregulation that can lead to either hypo- or hyperglycaemia. Here we identified feimin, encoded by a gene with a previously unknown function (B230219D22Rik in mice, C5orf24 in humans), as a key modulator of glucose homeostasis. Feimin is secreted from skeletal muscle during feeding and binds to its receptor, receptor protein tyrosine kinase Mer (MERTK), promoting glucose uptake and inhibiting glucose production by activation of AKT. Adm
2. Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial.
In a randomized, double-blind, placebo-controlled crossover trial in nondiabetic stone formers (n=53), empagliflozin reduced urinary relative supersaturation (RSR) for calcium phosphate by 36% in calcium stone formers and for uric acid by 30% in uric acid stone formers. No serious or prespecified adverse events occurred over the short treatment periods.
Impact: Demonstrates a repurposed metabolic therapy (SGLT2 inhibition) reduces validated urinary supersaturation surrogates in nondiabetic stone formers, opening a path to prevention trials.
Clinical Implications: Empagliflozin could become a preventive option for calcium phosphate and uric acid stones in nondiabetic patients, pending longer trials assessing stone recurrence, safety, and metabolic effects.
Key Findings
- Empagliflozin reduced RSR for calcium phosphate by 36% in calcium stone formers.
- Empagliflozin reduced RSR for uric acid by 30% in uric acid stone formers.
- No serious or prespecified adverse events were observed during 2-week treatment periods.
- Effect was specific by stone type; no significant changes in non-target RSRs.
Methodological Strengths
- Randomized, double-blind, placebo-controlled crossover design.
- Use of validated urinary supersaturation surrogates for stone recurrence.
Limitations
- Short treatment duration (2 weeks per period) and single-center design.
- Per-protocol primary analysis with modest sample size; clinical recurrence not assessed.
Future Directions: Conduct multicenter, longer-term RCTs powered for stone recurrence, safety, and patient-reported outcomes; explore mechanisms of reduced supersaturation in specific stone phenotypes.
Efficacy of sodium-glucose cotransporter 2 inhibitors for kidney stone prevention in nondiabetic patients is unknown. In a double-blind, placebo-controlled, single-center, crossover phase 2 trial, 53 adults (≥18 and <75 years) with calcium (n = 28) or uric acid (UA; n = 25) kidney stones (at least one previous kidney stone event) without diabetes (HbA1c < 6.5%, no diabetes treatment) were randomized to once daily empagliflozin 25 mg followed by placebo or reverse (2 weeks per treatment). Randomization and analysis were performed separately for both stone types. Primary ana
3. Mental Disorders Among Offspring Prenatally Exposed to Systemic Glucocorticoids.
In a nationwide cohort of 1,061,548 births, prenatal systemic glucocorticoid exposure was associated with increased risks of autism spectrum disorder, ADHD, and mood/anxiety/stress-related disorders by age 15, across maternal risk strata. Results remained in active-comparator and sibling analyses, though residual confounding by disease severity cannot be excluded.
Impact: Provides large-scale, methodologically robust evidence to inform risk–benefit discussions about systemic glucocorticoid use in pregnancy.
Clinical Implications: Counsel pregnant patients on potential neurodevelopmental and mood/anxiety risks with systemic glucocorticoids, emphasizing judicious use, lowest effective dose and duration, and alternative strategies when feasible.
Key Findings
- Among mothers at risk for preterm delivery, exposure increased ASD risk (6.6% vs 4.3%; RR 1.5), ADHD (5.8% vs 4.3%; RR 1.3), and mood/anxiety/stress disorders (7.2% vs 4.6%; RR 1.5).
- Among mothers with autoimmune/inflammatory disorders, exposure increased ASD (RR 1.3), ADHD (RR 1.3), and mood/anxiety/stress disorders (RR 1.4).
- Active comparator and sibling analyses supported the associations, though disease severity confounding remains possible.
Methodological Strengths
- Nationwide, population-based cohort with >1 million births and long follow-up.
- Use of active comparator and sibling designs to reduce confounding.
Limitations
- Observational design with potential residual confounding by disease severity and indication.
- Exposure and outcome ascertainment rely on registries; misclassification is possible.
Future Directions: Investigate dose–response, timing, and specific glucocorticoid agents; integrate mechanistic studies and causal inference methods to refine risk estimates.
IMPORTANCE: Current evidence of the association between prenatal exposure to glucocorticoids and long-term mental disorders is scarce and has limitations. OBJECTIVE: To investigate the association between prenatal exposure to systemic glucocorticoids and mental disorders in offspring at the age of 15 years, comparing exposed vs unexposed offspring born to mothers with the same underlying disease (risk of preterm delivery and autoimmune or inflammatory disorders). DESIGN, SETTING, AND PARTICIPANTS: This nationwide population-based cohort study used data from registries in Denmark with follow-up until December 31, 2018. Participants included all Danish infants born alive from 1996 to 2016. Analyses were performed from January to December 2023. EXPOSURES: Prenatal exposure to systemic glucocorticoids. MAIN OUTCOMES AND MEASURES: Fifteen-year crude and adjusted risks, risk differences, and risk ratios (RR) for mental disorders using Kaplan-Meier estimator comparing exposed vs unexposed offspring born to mothers with the same underlying disease. RESULTS: A total of 1 061 548 infants (52% male) were included in the final study cohort, including 31 518 born to mothers at risk of preterm delivery and 288 747 born to mothers with autoimmune or inflammatory disorders. Among offspring born to mothers at risk of preterm delivery, the adjusted risks for exposed vs unexposed were 6.6% vs 4.3% (RR, 1.5 [95% CI, 1.2-1.9]) for autism spectrum disorders; 1.6% vs 1.3% (RR, 1.3 [95% CI, 0.8-1.8]) for intellectual disabilities; 5.8% vs 4.3% (RR, 1.3 [95% CI, 1.0-1.7]) for attention-deficit hyperactivity disorder (ADHD); and 7.2% vs 4.6% (RR, 1.5 [95% CI, 1.1-2.0]) for mood, anxiety, and stress-related disorders. Among offspring born to mothers with autoimmune or inflammatory disorders, the adjusted risks for exposed vs unexposed were 4.8% vs 3.8% (RR, 1.3 [95% CI, 1.1-1.5]) for autism spectrum disorders; 1.1% vs 0.8% (RR 1.4, [95% CI, 0.9-2.0]) for intellectual disabilities; 5.5% vs 4.4% (RR, 1.3 [95% CI, 1.0-1.5]) for ADHD; and 6.6% vs 4.6% (RR, 1.4 [95% CI, 1.2-1.8]) for mood, anxiety, and stress-related disorders. Findings were confirmed through an active comparator and sibling design. However, confounding by disease severity could not be ruled out. CONCLUSIONS AND RELEVANCE: In this cohort study, prenatal exposure to glucocorticoids was associated with higher risk of some mental disorders. These data support continued caution in the use of glucocorticoids in pregnant people.